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. 2022 Apr;54(4):412-436.
doi: 10.1038/s41588-022-01024-z. Epub 2022 Apr 4.

New insights into the genetic etiology of Alzheimer's disease and related dementias

Céline Bellenguez #  1 , Fahri Küçükali #  2   3   4 , Iris E Jansen #  5   6 , Luca Kleineidam #  7   8   9 , Sonia Moreno-Grau #  10   11 , Najaf Amin #  12   13 , Adam C Naj #  14   15 , Rafael Campos-Martin #  8 , Benjamin Grenier-Boley  16 , Victor Andrade  7   8 , Peter A Holmans  17 , Anne Boland  18 , Vincent Damotte  16 , Sven J van der Lee  5   19 , Marcos R Costa  16   20 , Teemu Kuulasmaa  21 , Qiong Yang  22   23 , Itziar de Rojas  10   11 , Joshua C Bis  24 , Amber Yaqub  12 , Ivana Prokic  12 , Julien Chapuis  16 , Shahzad Ahmad  12   25 , Vilmantas Giedraitis  26 , Dag Aarsland  27   28 , Pablo Garcia-Gonzalez  10   11 , Carla Abdelnour  10   11 , Emilio Alarcón-Martín  10   29 , Daniel Alcolea  11   30 , Montserrat Alegret  10   11 , Ignacio Alvarez  31   32 , Victoria Álvarez  33   34 , Nicola J Armstrong  35 , Anthoula Tsolaki  36   37 , Carmen Antúnez  38 , Ildebrando Appollonio  39   40 , Marina Arcaro  41 , Silvana Archetti  42 , Alfonso Arias Pastor  43   44 , Beatrice Arosio  45   46 , Lavinia Athanasiu  47 , Henri Bailly  48 , Nerisa Banaj  49 , Miquel Baquero  50 , Sandra Barral  51   52   53 , Alexa Beiser  21   54 , Ana Belén Pastor  55 , Jennifer E Below  56 , Penelope Benchek  57   58 , Luisa Benussi  59 , Claudine Berr  60 , Céline Besse  18 , Valentina Bessi  61   62 , Giuliano Binetti  59   63 , Alessandra Bizarro  64 , Rafael Blesa  11   30 , Mercè Boada  10   11 , Eric Boerwinkle  65   66 , Barbara Borroni  67 , Silvia Boschi  68 , Paola Bossù  69 , Geir Bråthen  70   71 , Jan Bressler  65   72 , Catherine Bresner  17 , Henry Brodaty  35   73 , Keeley J Brookes  74 , Luis Ignacio Brusco  75   76   77 , Dolores Buiza-Rueda  11   78 , Katharina Bûrger  79   80 , Vanessa Burholt  81   82 , William S Bush  83 , Miguel Calero  10   55   84 , Laura B Cantwell  85 , Geneviève Chene  86   87 , Jaeyoon Chung  88 , Michael L Cuccaro  89 , Ángel Carracedo  90   91 , Roberta Cecchetti  92 , Laura Cervera-Carles  11   30 , Camille Charbonnier  93 , Hung-Hsin Chen  94 , Caterina Chillotti  95 , Simona Ciccone  46 , Jurgen A H R Claassen  96 , Christopher Clark  97 , Elisa Conti  39 , Anaïs Corma-Gómez  98 , Emanuele Costantini  99 , Carlo Custodero  100 , Delphine Daian  18 , Maria Carolina Dalmasso  8 , Antonio Daniele  99 , Efthimios Dardiotis  101 , Jean-François Dartigues  102 , Peter Paul de Deyn  103 , Katia de Paiva Lopes  104   105   106   107 , Lot D de Witte  107 , Stéphanie Debette  102 , Jürgen Deckert  108 , Teodoro Del Ser  55 , Nicola Denning  109 , Anita DeStefano  21   22   110 , Martin Dichgans  79   111 , Janine Diehl-Schmid  112 , Mónica Diez-Fairen  31   32 , Paolo Dionigi Rossi  46 , Srdjan Djurovic  47 , Emmanuelle Duron  48 , Emrah Düzel  113   114 , Carole Dufouil  86   87 , Gudny Eiriksdottir  115 , Sebastiaan Engelborghs  116   117   118   119 , Valentina Escott-Price  15   109 , Ana Espinosa  10   11 , Michael Ewers  79   80 , Kelley M Faber  120 , Tagliavini Fabrizio  121 , Sune Fallgaard Nielsen  122 , David W Fardo  123 , Lucia Farotti  124 , Chiara Fenoglio  125 , Marta Fernández-Fuertes  98 , Raffaele Ferrari  126   127 , Catarina B Ferreira  128 , Evelyn Ferri  46 , Bertrand Fin  18 , Peter Fischer  129 , Tormod Fladby  130 , Klaus Fließbach  8   9 , Bernard Fongang  131 , Myriam Fornage  71   72 , Juan Fortea  11   30 , Tatiana M Foroud  120 , Silvia Fostinelli  59 , Nick C Fox  132 , Emlio Franco-Macías  133 , María J Bullido  11   134   135 , Ana Frank-García  11   134   136 , Lutz Froelich  137 , Brian Fulton-Howard  138 , Daniela Galimberti  41   125 , Jose Maria García-Alberca  11   139 , Pablo García-González  10 , Sebastian Garcia-Madrona  140 , Guillermo Garcia-Ribas  140 , Roberta Ghidoni  59 , Ina Giegling  141 , Giaccone Giorgio  121 , Alison M Goate  138 , Oliver Goldhardt  112 , Duber Gomez-Fonseca  142 , Antonio González-Pérez  143 , Caroline Graff  144   145 , Giulia Grande  146 , Emma Green  147 , Timo Grimmer  112 , Edna Grünblatt  148   149   150 , Michelle Grunin  58 , Vilmundur Gudnason  151 , Tamar Guetta-Baranes  152 , Annakaisa Haapasalo  153 , Georgios Hadjigeorgiou  154 , Jonathan L Haines  83 , Kara L Hamilton-Nelson  155 , Harald Hampel  156 , Olivier Hanon  48 , John Hardy  127 , Annette M Hartmann  141 , Lucrezia Hausner  137 , Janet Harwood  17 , Stefanie Heilmann-Heimbach  157 , Seppo Helisalmi  158   159 , Michael T Heneka  7   9 , Isabel Hernández  10   11 , Martin J Herrmann  108 , Per Hoffmann  157 , Clive Holmes  160 , Henne Holstege  5   19 , Raquel Huerto Vilas  43   44 , Marc Hulsman  5   19 , Jack Humphrey  104   105   106   161 , Geert Jan Biessels  162 , Xueqiu Jian  131 , Charlotte Johansson  144 , Gyungah R Jun  88 , Yuriko Kastumata  163 , John Kauwe  164 , Patrick G Kehoe  165 , Lena Kilander  22 , Anne Kinhult Ståhlbom  144 , Miia Kivipelto  166   167   168   169 , Anne Koivisto  158   170   171 , Johannes Kornhuber  172 , Mary H Kosmidis  173 , Walter A Kukull  174 , Pavel P Kuksa  15 , Brian W Kunkle  154 , Amanda B Kuzma  85 , Carmen Lage  11   175 , Erika J Laukka  146   176 , Lenore Launer  177   178 , Alessandra Lauria  64 , Chien-Yueh Lee  15 , Jenni Lehtisalo  158   179 , Ondrej Lerch  180   181 , Alberto Lleó  11   30 , William Longstreth Jr  182 , Oscar Lopez  23 , Adolfo Lopez de Munain  11   183 , Seth Love  165 , Malin Löwemark  22 , Lauren Luckcuck  17 , Kathryn L Lunetta  21 , Yiyi Ma  19   184 , Juan Macías  98 , Catherine A MacLeod  185 , Wolfgang Maier  7   9 , Francesca Mangialasche  166 , Marco Spallazzi  52 , Marta Marquié  10   11 , Rachel Marshall  17 , Eden R Martin  155 , Angel Martín Montes  11   134   136 , Carmen Martínez Rodríguez  34 , Carlo Masullo  186 , Richard Mayeux  51   187 , Simon Mead  188 , Patrizia Mecocci  92 , Miguel Medina  11   55 , Alun Meggy  109 , Shima Mehrabian  53 , Silvia Mendoza  139 , Manuel Menéndez-González  34 , Pablo Mir  11   189 , Susanne Moebus  190 , Merel Mol  78 , Laura Molina-Porcel  191   192 , Laura Montrreal  10 , Laura Morelli  193 , Fermin Moreno  11   183 , Kevin Morgan  194 , Thomas Mosley  195 , Markus M Nöthen  157 , Carolina Muchnik  75   196 , Shubhabrata Mukherjee  197 , Benedetta Nacmias  61   198 , Tiia Ngandu  179 , Gael Nicolas  93 , Børge G Nordestgaard  122   199 , Robert Olaso  18 , Adelina Orellana  10   11 , Michela Orsini  99 , Gemma Ortega  10   11 , Alessandro Padovani  66 , Caffarra Paolo  200 , Goran Papenberg  146 , Lucilla Parnetti  124 , Florence Pasquier  201 , Pau Pastor  31   32 , Gina Peloso  21   54 , Alba Pérez-Cordón  10 , Jordi Pérez-Tur  11   202   203 , Pierre Pericard  204 , Oliver Peters  205   206 , Yolande A L Pijnenburg  5 , Juan A Pineda  98 , Gerard Piñol-Ripoll  43   44 , Claudia Pisanu  207 , Thomas Polak  108 , Julius Popp  208   209   210 , Danielle Posthuma  6 , Josef Priller  206   211 , Raquel Puerta  10 , Olivier Quenez  93 , Inés Quintela  90 , Jesper Qvist Thomassen  212 , Alberto Rábano  11   55 , Innocenzo Rainero  67 , Farid Rajabli  155 , Inez Ramakers  213 , Luis M Real  98   214 , Marcel J T Reinders  215 , Christiane Reitz  187   215   216 , Dolly Reyes-Dumeyer  184   216 , Perry Ridge  217 , Steffi Riedel-Heller  218 , Peter Riederer  219 , Natalia Roberto  10 , Eloy Rodriguez-Rodriguez  11   175 , Arvid Rongve  220   221 , Irene Rosas Allende  33   34 , Maitée Rosende-Roca  10   11 , Jose Luis Royo  222 , Elisa Rubino  223 , Dan Rujescu  141 , María Eugenia Sáez  143 , Paraskevi Sakka  224 , Ingvild Saltvedt  70   225 , Ángela Sanabria  10   11 , María Bernal Sánchez-Arjona  133 , Florentino Sanchez-Garcia  226 , Pascual Sánchez Juan  11   175 , Raquel Sánchez-Valle  227 , Sigrid B Sando  69   70 , Chloé Sarnowski  65 , Claudia L Satizabal  22   110   131 , Michela Scamosci  92 , Nikolaos Scarmeas  51   228 , Elio Scarpini  41   125 , Philip Scheltens  5 , Norbert Scherbaum  229 , Martin Scherer  230 , Matthias Schmid  9   231 , Anja Schneider  7   9 , Jonathan M Schott  132 , Geir Selbæk  130   232 , Davide Seripa  233 , Manuel Serrano  234 , Jin Sha  14 , Alexey A Shadrin  47 , Olivia Skrobot  165 , Susan Slifer  155 , Gijsje J L Snijders  107 , Hilkka Soininen  158 , Vincenzo Solfrizzi  100 , Alina Solomon  158   166 , Yeunjoo Song  58 , Sandro Sorbi  61   198 , Oscar Sotolongo-Grau  10 , Gianfranco Spalletta  49 , Annika Spottke  9   235 , Alessio Squassina  236 , Eystein Stordal  237 , Juan Pablo Tartan  10 , Lluís Tárraga  10   11 , Niccolo Tesí  5   19 , Anbupalam Thalamuthu  35 , Tegos Thomas  36   37 , Giuseppe Tosto  51   184 , Latchezar Traykov  53 , Lucio Tremolizzo  39   40 , Anne Tybjærg-Hansen  199   212 , Andre Uitterlinden  238 , Abbe Ullgren  144 , Ingun Ulstein  232 , Sergi Valero  10   11 , Otto Valladares  15 , Christine Van Broeckhoven  2   3   239 , Jeffery Vance  89 , Badri N Vardarajan  51 , Aad van der Lugt  240 , Jasper Van Dongen  2   3   4 , Jeroen van Rooij  78   240 , John van Swieten  78 , Rik Vandenberghe  241   242 , Frans Verhey  213 , Jean-Sébastien Vidal  48 , Jonathan Vogelgsang  243   244 , Martin Vyhnalek  180   181 , Michael Wagner  7   9 , David Wallon  245 , Li-San Wang  15 , Ruiqi Wang  21   22 , Leonie Weinhold  231 , Jens Wiltfang  243   246   247 , Gill Windle  185 , Bob Woods  185 , Mary Yannakoulia  248 , Habil Zare  131 , Yi Zhao  15 , Xiaoling Zhang  249 , Congcong Zhu  249 , Miren Zulaica  11   250 ; EADB; GR@ACE; DEGESCO; EADI; GERAD; Demgene; FinnGen; ADGC; CHARGE; Lindsay A Farrer  21   88   110 , Bruce M Psaty  23   85   251 , Mohsen Ghanbari  12 , Towfique Raj  104   105   106   161 , Perminder Sachdev  35 , Karen Mather  35 , Frank Jessen  7   9 , M Arfan Ikram  12 , Alexandre de Mendonça  128 , Jakub Hort  178   180 , Magda Tsolaki  36   37 , Margaret A Pericak-Vance  153 , Philippe Amouyel  16 , Julie Williams  17   109 , Ruth Frikke-Schmidt  199   212 , Jordi Clarimon  11   30 , Jean-François Deleuze  18 , Giacomina Rossi  121 , Sudha Seshadri  22   110   131 , Ole A Andreassen  47 , Martin Ingelsson  26 , Mikko Hiltunen #  20 , Kristel Sleegers #  2   3   4 , Gerard D Schellenberg #  15 , Cornelia M van Duijn #  12   13 , Rebecca Sims #  17 , Wiesje M van der Flier #  5 , Agustín Ruiz #  10   11 , Alfredo Ramirez #  7   8   9   131   252 , Jean-Charles Lambert #  253
Collaborators, Affiliations

New insights into the genetic etiology of Alzheimer's disease and related dementias

Céline Bellenguez et al. Nat Genet. 2022 Apr.

Abstract

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

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Conflict of interest statement

H. Hampel is an employee of Eisai. The present article was initiated and prepared as part of his academic position at Sorbonne University (Paris, France), and it reflects entirely and exclusively his own opinion. He serves as Senior Associate Editor for the Alzheimers & Dementia journal and has not received any fees or honoraria since May 2019. Before May 2019, H. Hampel received lecture fees from Servier, Biogen and Roche; research grants from Pfizer, Avid and MSD Avenir (paid to the institution); travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and Company, Takeda, Zinfandel Pharmaceuticals, GE Healthcare and Oryzon Genomics; and consultancy fees from Qynapse, Jung Diagnostics, Cytox, Axovant, Anavex, Takeda, Zinfandel Pharmaceuticals, GE Healthcare, Oryzon Genomics and Functional Neuromodulation. He served as a scientific advisory board member for Functional Neuromodulation, Axovant, Eisai, Eli Lilly and Company, Cytox, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. The remaining authors declare no competing interests

Figures

Fig. 1
Fig. 1. Manhattan plot of the stage I results.
P values are two-sided raw P values derived from a fixed-effect meta-analysis. Variants with a P value below 1 × 10−36 are not shown. Loci with a genome-wide significant signal are annotated (known loci in black and new loci in red). Variants in new loci are highlighted in red. The red dotted line represents the genome-wide significance level (P = 5 × 10−8), and the black dotted line represents the suggestive significance level (P = 1 × 10−5).
Fig. 2
Fig. 2. Gene prioritization.
a, Summary of weighted scores for each evidence category for the prioritized genes in the 42 new genome-wide-significant loci. Using our gene prioritization method, we considered the genes within 1 Mb of each new lead variant and prioritized a total of 55 genes in 42 new loci at two different confidence levels (31 tier 1 genes and 24 tier 2 genes). The leftmost squares indicate the new locus index number. The different types of evidence are colored according to the seven different domains to which they belonged. Weighted scores for each evidence category are rescaled to a 0–100 scale, and the proportions of mean human brain cell-type-specific expression for each gene are also rescaled to a 0–100 scale; darker colors represent higher scores or higher expression proportions. Tier 1 genes are shown in dark green, and tier 2 genes are shown in light green. Only tier 1 and tier 2 genes are shown for each locus. Supplementary Fig. 35 shows full results. MAFs and CADD (v1.6) PHRED scores for rare and/or protein-altering rare variants are labeled in white within the respective squares. b, Pathway enrichment analysis based on the tier 1 gene list. Only the ten strongest associations (according to STRING software) are presented here. coloc, colocalization; eQTL, expression QTL; eTWAS, expression transcriptome-wide association study; GO, Gene Ontology; haQTL, histone acetylation QTL; Mon. Mac., monocytes and macrophages; sTWAS, splicing transcriptome-wide association study; m/haQTL, methylation/histone acetylation QTL; sQTL, splicing QTL; FDR, false discovery rate.
Fig. 3
Fig. 3. Regulation of EGFR expression by the ADD-risk-associated and colocalized brain eQTLs within the intergenic SEC61G locus.
a, The regional plot of the new SEC61G locus (L18) shows the EADB GWAS stage I (n = 487,511) ADD association signal within 200 kb of the intergenic lead variant, rs76928645 (the two closest protein-coding genes, SEC61G and EGFR, are more than 100 kb from the lead variant), together with the eQTLs in the same region identified for SEC61G and EGFR expression separately in the TCX (MayoRNAseq TCX eQTL catalog based on n = 259 individuals). The rs7692864 lead variant is shown in purple, and LD r2 values (calculated for the EADB Trans-Omics for Precision Medicine (TOPMed) dataset (n = 42,140) with respect to the lead variant) are indicated on a color scale. y axis, −log10 for the GWAS or eQTL P value; x axis, hg38 genomic position on chromosome 7. b, Colocalization between the EGFR eQTL signal (MayoRNAseq TCX, n = 259 individuals) and the EADB GWAS stage I (n = 487,511) signal (eQTL coloc PP4 = 98.3%); with the significant eTWAS association (eTWAS P = 6.9 × 10−9 and eTWAS Z = 5.8) and fine-mapped (FOCUS PIP = 1) eTWAS association in the same catalog. y axis, eQTL −log10(P) value; x axis, GWAS −log10(P) value. LD r2 values and color scales are as in a. c, The eQTL violin plot shows a significant association (eQTL P = 3 × 10−18) between the rs76928645 lead variant genotype and EGFR expression in the TCX (MayoRNAseq TCX, n = 259 individuals), where the protective allele T is associated with lower EGFR expression (eQTL β, −0.39). Each data point represents a sample whose normalized EGFR expression value is indicated on the y axis, and the rs76928645 genotype information is indicated on the x axis. The lower and upper hinges of the boxes represent the first and third quantiles, the whiskers extend 1.5 times the interquartile range from the hinges and the line represents the median.
Fig. 4
Fig. 4. Focus on TSPAN14 locus.
a, Splicing QTL (sQTL)-GWAS integration results. Known TSPAN14 transcripts (GENCODE v38; green, coding sequences; gray, noncoding) plotted with −log10(P) for (1) EADB GWAS stage I (n = 487,511) signal (black), (2) sQTL signal for chr10:80509471–80510106 junction (supporting cryptic exon 1) in the EADB Belgian LCL sQTL catalog (n = 70 individuals, blue) and (3) sQTL signal for chr10:80512269–80512719 junction in the MayoRNAseq TCX sQTL catalog (n = 259 individuals, red); hg38 genomic position is shown above. LCL and brain-based sQTL coloc and sTWAS analyses associate ADD risk with these junctions that suggest cryptic splicing within ADAM10-interacting domain of TSPAN14 (magenta), which was predicted to result in two cryptic exons. b, Long-read sequencing validation of TSPAN14 cryptic exons. Nanopore sequencing results (Supplementary Note) in the zoomed-in region of chr10:80506973–80516400 (cumulative coverage in log10 scale). Pooled LCL cDNA sample sequenced for cDNA Amplicon2 shown in blue. cDNA Amplicon1 was sequenced on biologically independent hippocampal (HPC; n = 16, red), frontal cortex (FC; n = 18, pink) and LCL (n = 59, orange) cDNA samples. Green, canonical exons (8–12); dotted black lines, canonical splicing; blue, cryptic exon 1 (>45 bp); red, cryptic exon 2 (118 bp). All annotated junctions use canonical splice donor (GT) and acceptor (AG) sites. c,d, sQTL-GWAS colocalization plots for chr10:80509471–80510106 (supporting cryptic exon 1) in the EADB Belgian LCL sQTL catalog (n = 70 individuals) (c) and chr10:80512269–80512719 (supporting cryptic exon 2) in the MayoRNAseq TCX sQTL catalog (n = 259 individuals) (d). sQTL signals for the two junctions colocalize with ADD signal (PP4s of 98.8% and 97.4%, respectively), and sTWAS associates with increased preference for the cryptic splicing with decreased ADD risk (sTWAS P = 6.28 × 10−12 and 1.6 × 10−13, sTWAS Z = −6.9 and −7.4, respectively). y axis, sQTL −log10(P); x axis, EADB GWAS stage I −log10(P). LD r2 values calculated within EADB-TOPMed dataset (n = 42,140) based on the lead variant rs6586028 (purple) are indicated on a color scale.
Fig. 5
Fig. 5. Association between the GRS and the risk of progression to AD.
a,b, Meta-analysis results of the association between the GRS and the risk of progression to AD in population-based cohorts (n = 17,545 independent samples) (a) and MCI cohorts (n = 4,114 independent samples) (b). Data are presented as HR together with 95% CIs derived from Cox regression analyses for each individual cohort. HRs indicate the effect of the GRS as the increment in the AD risk associated with each additional average risk allele in the GRS. Null hypothesis testing is based on a meta-analysis of individual cohort effects using fixed effects (FE) and random effects (RE) models. Resulting HRs and 95% CIs and the respective Z test and associated two-sided P value are shown at the bottom of the figure. Heterogeneity between cohorts is indicated by the I2 index together with the respective Cochran’s Q statistic (distributed as χ² statistic), associated degrees of freedom and P value. 3C, Three-City Study; AgeCoDe, German study on aging cognition and dementia; AMC, additional, independent memory clinic cohort from Fundacio ACE; DCN, German Dementia Competence Network study; FACE, Fundacio ACE memory clinic cohort; FHS, Framingham Heart Study; HAN, BALTAZAR multicenter prospective memory clinic study; MAS, Sydney Memory and Ageing Study; RS1, Rotterdam Study first cohort; RS2, Rotterdam Study second cohort; VITA, Vienna Transdanube Aging study; UAN, memory clinic cohort from the Hospital Network Antwerp; UHA, University of Halle memory clinic cohort; ZIM, Heidelberg/Mannheim memory clinic sample.
Fig. 6
Fig. 6. Risk of progression to AD according to the GRS.
a,b, Representative plots of the progression to AD over 10 years in the population-based 3C study (a) and the progression from MCI to AD over 5 years in the Fundació ACE cohort (b). The figures show the probabilities of conversion (survival probabilities) to AD (y axes) for a hypothetical participant with average covariates (mean values for age and PCs, and the mode for sex and APOE) and a GRS at the first (lowest) decile (in blue) or a GRS at the ninth (highest) decile (red). The shaded regions correspond to the 95% CI.
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